Experts Debate: Is HIV Cure "Hype or Hope"?

Is a functional cure for HIV feasible within the foreseeable future or is it a hopeless quest robbing resources from more practical approaches to improve the lives of people living with HIV? This question was the crux of a mock trial held on the opening day of the 14th European AIDS Conference in Brussels.

The debate was part of a satellite session sponsored by Bristol-Myers Squibb (BMS) to mark the launch of its new Partnering for Cure initiative, which will support education and research into novel treatment and cure strategies for chronic viral diseases including HIV and hepatitis B and C.

Christine Katlama of Pierre and Marie Curie University in Paris, playing the 'judge', noted the recent increase in attention to the possibility of an HIV cure at scientific meetings and in the popular media, spurred in part by 'proof-of-concept' cases like that of Timothy Ray Brown (the 'Berlin patient') and that of the Mississippi baby.
Speaking in defence of the proposition that an HIV cure is possible, Carlo Federico Perno of the University of Rome gave the example of hepatitis C as a virus that can be eradicated.

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Whilst traditional interferon-based therapy relied on stimulating the immune response, new direct-acting agents work by interfering with various steps of the hepatitis C virus (HCV) lifecycle, much like combination antiretroviral therapy (ART) for HIV. Two highly effective and well-tolerated compounds -- Janssen's simeprevir and Gilead Sciences' sofosbuvir -- are scheduled for US approval by the end of the year (assuming the federal government shutdown does not disrupt the work of the Food and Drug Administration).

The inclusion of this argument was no doubt intended as an opportunity to educate about hepatitis C, which is increasingly making its way into HIV conferences. Many people with HIV have hepatitis C co-infection, and HIV clinicians are increasingly called upon to treat it. BMS has some promising hepatitis C direct-acting agents in the pipeline including the NS5A inhibitor daclatasvir, the HCV protease inhibitor asunaprevir and the non-nucleoside polymerase inhibitor BMS-791325.

But no one, including Perno, really thinks hepatitis is a good model for an HIV cure.

HCV remains confined to a cell's cytoplasm, where it must either "replicate or die", Perno explained. If it does not do so immediately, HCV RNA is rapidly degraded; drugs that fully halt replication can therefore offer a permanent cure. Perhaps the main scientific barrier to hepatitis C treatment is that the virus is highly variable -- much more so than HIV -- which means different drugs work best against different HCV genotypes and combination therapy is needed to prevent resistance.

HIV, in contrast, enters host cell chromosomes where it may remain latent for decades and perhaps even a lifetime. Speaking for the 'prosecution', José Alcamí of the European University of Madrid said that viral latency, existence of viral reservoirs and destruction of the immune system by the virus are the three main barriers to a cure.
HIV DNA in resting CD4 T-cells can awaken when these cells become activated as part of an immune response, leading to renewed viral replication, he explained. For this reason people with HIV must remain on ART -- for life, as far as we know -- to guard against viral rebound.

HIV cure researchers are testing several dif-ferent strategies to reverse latency and flush the virus out of hiding. The so-called "shock and kill" approach involves using agents such as HDAC inhibitors to awaken latent virus coupled with immune-boosting therapies to kill infected cells. But current anti-latency drugs trigger only weak viral reactivation and target only a small proportion of the viral reservoir.

In addition to long-lived memory T-cells, the HIV reservoir also includes anatomical sites such as the lymph nodes, gut lymphoid tissue and central nervous system. HIV preferentially targets CD4 cells -- the "brain of the immune system" -- and persistent immune activation caused by the virus leads to immune senescence and eventual exhaustion of immune function, Alcamí said.

"I would like to give good news, but we face a virus we are not able to cure with drugs we have available or even drugs we may have in the future," he concluded. "The destruction of the immune system remains a barrier to a cure."

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